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- PDB-6u7c: Human GRK2 in complex with Gbetagamma subunits and CCG258747 -

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Basic information

Entry
Database: PDB / ID: 6u7c
TitleHuman GRK2 in complex with Gbetagamma subunits and CCG258747
Components
  • (Guanine nucleotide-binding protein ...) x 2
  • Beta-adrenergic receptor kinase 1
KeywordsTRANSFERASE/SIGNALING PROTEIN / G-protein coupled receptor kinase / kinase inhibitor / SIGNALING PROTEIN / TRANSFERASE-SIGNALING PROTEIN complex
Function / homology
Function and homology information


negative regulation of the force of heart contraction by chemical signal / negative regulation of relaxation of smooth muscle / beta-adrenergic-receptor kinase / Edg-2 lysophosphatidic acid receptor binding / alpha-2A adrenergic receptor binding / beta-adrenergic receptor kinase activity / G protein-coupled receptor kinase activity / tachykinin receptor signaling pathway / Olfactory Signaling Pathway / Sensory perception of sweet, bitter, and umami (glutamate) taste ...negative regulation of the force of heart contraction by chemical signal / negative regulation of relaxation of smooth muscle / beta-adrenergic-receptor kinase / Edg-2 lysophosphatidic acid receptor binding / alpha-2A adrenergic receptor binding / beta-adrenergic receptor kinase activity / G protein-coupled receptor kinase activity / tachykinin receptor signaling pathway / Olfactory Signaling Pathway / Sensory perception of sweet, bitter, and umami (glutamate) taste / negative regulation of striated muscle contraction / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / positive regulation of catecholamine secretion / desensitization of G protein-coupled receptor signaling pathway / Activation of SMO / cytoplasmic side of mitochondrial outer membrane / Activation of the phototransduction cascade / regulation of the force of heart contraction / Calmodulin induced events / Activation of G protein gated Potassium channels / G-protein activation / G beta:gamma signalling through PI3Kgamma / Prostacyclin signalling through prostacyclin receptor / G beta:gamma signalling through PLC beta / ADP signalling through P2Y purinoceptor 1 / Thromboxane signalling through TP receptor / Presynaptic function of Kainate receptors / G beta:gamma signalling through CDC42 / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / G alpha (12/13) signalling events / Glucagon-type ligand receptors / G beta:gamma signalling through BTK / ADP signalling through P2Y purinoceptor 12 / Adrenaline,noradrenaline inhibits insulin secretion / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / Ca2+ pathway / Thrombin signalling through proteinase activated receptors (PARs) / G alpha (z) signalling events / Extra-nuclear estrogen signaling / G alpha (s) signalling events / G alpha (q) signalling events / G alpha (i) signalling events / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / Vasopressin regulates renal water homeostasis via Aquaporins / cardiac muscle contraction / viral genome replication / G protein-coupled receptor binding / receptor internalization / G protein-coupled acetylcholine receptor signaling pathway / photoreceptor disc membrane / cellular response to catecholamine stimulus / adenylate cyclase-activating dopamine receptor signaling pathway / Cargo recognition for clathrin-mediated endocytosis / cellular response to prostaglandin E stimulus / G-protein beta-subunit binding / heterotrimeric G-protein complex / sensory perception of taste / presynapse / signaling receptor complex adaptor activity / heart development / retina development in camera-type eye / GTPase binding / G alpha (s) signalling events / phospholipase C-activating G protein-coupled receptor signaling pathway / G alpha (q) signalling events / cell population proliferation / protein kinase activity / postsynapse / cilium / G protein-coupled receptor signaling pathway / GTPase activity / synapse / symbiont entry into host cell / protein-containing complex binding / ATP binding / membrane / plasma membrane / cytoplasm / cytosol
Similarity search - Function
Helix Hairpins - #1270 / Transducin (heterotrimeric G protein), gamma chain / G Protein Gi Gamma 2 / GPCR kinase / Regulator of G-protein Signalling 4, domain 2 / Regulator of G-protein Signalling 4; domain 2 / Regulator of G protein signaling domain / RGS domain / RGS domain profile. / Regulator of G protein signalling domain ...Helix Hairpins - #1270 / Transducin (heterotrimeric G protein), gamma chain / G Protein Gi Gamma 2 / GPCR kinase / Regulator of G-protein Signalling 4, domain 2 / Regulator of G-protein Signalling 4; domain 2 / Regulator of G protein signaling domain / RGS domain / RGS domain profile. / Regulator of G protein signalling domain / RGS, subdomain 2 / RGS domain superfamily / Pleckstrin-homology domain (PH domain)/Phosphotyrosine-binding domain (PTB) / PH-domain like / Extension to Ser/Thr-type protein kinases / AGC-kinase, C-terminal / AGC-kinase C-terminal domain profile. / PH domain / PH domain profile. / Pleckstrin homology domain. / YVTN repeat-like/Quinoprotein amine dehydrogenase / Pleckstrin homology domain / 7 Propeller / Methylamine Dehydrogenase; Chain H / Few Secondary Structures / Irregular / G-protein, gamma subunit / G-protein gamma subunit domain profile. / G-protein gamma-like domain / G-protein gamma-like domain superfamily / GGL domain / G protein gamma subunit-like motifs / GGL domain / G protein beta WD-40 repeat protein / Guanine nucleotide-binding protein, beta subunit / G-protein, beta subunit / Helix Hairpins / PH-like domain superfamily / WD domain, G-beta repeat / Roll / G-protein beta WD-40 repeat / WD40 repeat, conserved site / Phosphorylase Kinase; domain 1 / Trp-Asp (WD) repeats signature. / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / WD40 repeats / WD40 repeat / Protein kinase domain / WD40-repeat-containing domain superfamily / Serine/Threonine protein kinases, catalytic domain / WD40/YVTN repeat-like-containing domain superfamily / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily / 2-Layer Sandwich / Orthogonal Bundle / Mainly Beta / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-Q1Y / Beta-adrenergic receptor kinase 1 / Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
Similarity search - Component
Biological speciesHomo sapiens (human)
Bos taurus (domestic cattle)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.44 Å
AuthorsBouley, R. / Tesmer, J.J.G.
Funding support United States, 3items
OrganizationGrant numberCountry
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)HL071818 United States
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)HL122416 United States
American Heart Association18POST33960047
CitationJournal: Mol.Pharmacol. / Year: 2020
Title: A New Paroxetine-Based GRK2 Inhibitor Reduces Internalization of themu-Opioid Receptor.
Authors: Bouley, R.A. / Weinberg, Z.Y. / Waldschmidt, H.V. / Yen, Y.C. / Larsen, S.D. / Puthenveedu, M.A. / Tesmer, J.J.G.
History
DepositionSep 2, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 15, 2020Provider: repository / Type: Initial release
Revision 1.1May 20, 2020Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title / _citation_author.identifier_ORCID
Revision 1.2Oct 11, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Beta-adrenergic receptor kinase 1
B: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
G: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)125,4815
Polymers124,9553
Non-polymers5272
Water1,36976
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area6910 Å2
ΔGint-49 kcal/mol
Surface area47170 Å2
MethodPISA
Unit cell
Length a, b, c (Å)60.633, 240.610, 214.576
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number20
Space group name H-MC2221
Symmetry operation#1: x,y,z
#2: x,-y,-z
#3: -x,y,-z+1/2
#4: -x,-y,z+1/2
#5: x+1/2,y+1/2,z
#6: x+1/2,-y+1/2,-z
#7: -x+1/2,y+1/2,-z+1/2
#8: -x+1/2,-y+1/2,z+1/2

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Components

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Protein , 1 types, 1 molecules A

#1: Protein Beta-adrenergic receptor kinase 1 / Beta-ARK-1 / G-protein coupled receptor kinase 2


Mass: 79692.641 Da / Num. of mol.: 1 / Mutation: C68S
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GRK2, ADRBK1, BARK, BARK1
Production host: Spodoptera aff. frugiperda 2 RZ-2014 (butterflies/moths)
References: UniProt: P25098, beta-adrenergic-receptor kinase

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Guanine nucleotide-binding protein ... , 2 types, 2 molecules BG

#2: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Transducin beta chain 1


Mass: 37416.930 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Bos taurus (domestic cattle) / Gene: GNB1
Production host: Spodoptera aff. frugiperda 2 RZ-2014 (butterflies/moths)
References: UniProt: P62871
#3: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 / G gamma-I


Mass: 7845.078 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Bos taurus (domestic cattle) / Gene: GNG2
Production host: Spodoptera aff. frugiperda 2 RZ-2014 (butterflies/moths)
References: UniProt: P63212

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Non-polymers , 3 types, 78 molecules

#4: Chemical ChemComp-Q1Y / 5-[(3S,4R)-3-{[(2H-1,3-benzodioxol-5-yl)oxy]methyl}piperidin-4-yl]-2-fluoro-N-[(2H-indazol-3-yl)methyl]benzamide


Mass: 502.537 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C28H27FN4O4 / Feature type: SUBJECT OF INVESTIGATION
#5: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Formula: Mg
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 76 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 3.13 Å3/Da / Density % sol: 60.72 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 6 / Details: 50 mM MES pH 6.0, 1.1 M NaCl, 6% PEG 3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-D / Wavelength: 1.0332 Å
DetectorType: MARMOSAIC 300 mm CCD / Detector: CCD / Date: Nov 10, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.0332 Å / Relative weight: 1
ReflectionResolution: 2.44→57.92 Å / Num. obs: 112767 / % possible obs: 99.22 % / Redundancy: 13.5 % / CC1/2: 0.997 / Rmerge(I) obs: 0.2367 / Rpim(I) all: 0.06825 / Rrim(I) all: 0.2521 / Net I/σ(I): 7.25
Reflection shellResolution: 2.44→2.527 Å / Rmerge(I) obs: 3.939 / Mean I/σ(I) obs: 0.47 / Num. unique obs: 5845 / CC1/2: 0.405 / Rpim(I) all: 1.592 / % possible all: 95.66

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Processing

Software
NameVersionClassification
PHENIX1.13_2998refinement
DIALSdata reduction
DIALSdata scaling
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4PNK

4pnk


Resolution: 2.44→29.902 Å / SU ML: 0.51 / Cross valid method: THROUGHOUT / σ(F): 1.33 / Phase error: 37.12
RfactorNum. reflection% reflection
Rfree0.2624 3708 3.39 %
Rwork0.2366 --
obs0.2375 109470 97.03 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 210.7 Å2 / Biso mean: 52.51 Å2 / Biso min: 41.34 Å2
Refinement stepCycle: final / Resolution: 2.44→29.902 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8213 0 38 76 8327
Biso mean--80.96 66.18 -
Num. residues----1028
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
2.44-2.47210.45761220.4315330179
2.4721-2.50590.37531230.4258347583
2.5059-2.54170.44551270.4139377290
2.5417-2.57960.43211340.434397295
2.5796-2.61990.44291390.4352409897
2.6199-2.66290.41211400.4345400296
2.6629-2.70870.47531430.4237407596
2.7087-2.7580.49471480.416409097
2.758-2.8110.4091360.389402298
2.811-2.86830.35151450.3834414398
2.8683-2.93060.3891490.3619412799
2.9306-2.99870.40141470.3609414399
2.9987-3.07360.39181470.3586420099
3.0736-3.15670.39751430.33594176100
3.1567-3.24940.32721480.30334153100
3.2494-3.35420.27571480.27244213100
3.3542-3.47390.30481410.264100100
3.4739-3.61280.25741460.23454216100
3.6128-3.77690.23211480.20594205100
3.7769-3.97560.20561510.18824177100
3.9756-4.2240.18891420.16834170100
4.224-4.54910.18521470.14834193100
4.5491-5.0050.171500.13934211100
5.005-5.72480.19091470.1634147100
5.7248-7.19610.21461440.18424211100
7.1961-29.9020.17671530.1537417099
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
13.3439-1.4246-2.13732.77951.97043.8449-0.4066-0.3602-0.69940.0221-0.18220.63770.6604-0.17250.45180.9520.06410.29880.44350.07580.9886-44.7213.08632.311
27.9656-0.4532-1.52815.82221.4335.7406-0.1652-0.02970.1489-0.90290.2106-0.46610.31331.1568-0.09880.81830.1280.14580.48560.02020.5518-18.05918.76415.848
34.1738-1.2422-1.0415.3298-0.41413.89290.0778-0.82910.81430.04820.2854-0.7236-0.65741.1548-0.32450.7097-0.11510.08470.687-0.26310.6854-21.23336.31733.246
42.1738-0.21750.16996.5464-0.84941.77860.2730.40110.1755-0.6255-0.0615-0.4129-0.42160.0781-0.07461.32460.13690.33310.42470.04760.9205-22.013-21.79615.914
51.3198-1.10210.19783.2258-0.54391.40740.17520.1199-0.171-0.5274-0.00850.30280.0843-0.0917-0.1370.96670.00960.10770.3133-0.00350.7139-24.794-55.90126.892
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1( CHAIN A AND ( RESID 30:184 OR RESID 513:547 ) )A30 - 184
2X-RAY DIFFRACTION1( CHAIN A AND ( RESID 30:184 OR RESID 513:547 ) )A513 - 547
3X-RAY DIFFRACTION2( CHAIN A AND ( RESID 185:274 OR RESID 475:512 OR RESID 701:701 ) )A185 - 274
4X-RAY DIFFRACTION2( CHAIN A AND ( RESID 185:274 OR RESID 475:512 OR RESID 701:701 ) )A475 - 512
5X-RAY DIFFRACTION2( CHAIN A AND ( RESID 185:274 OR RESID 475:512 OR RESID 701:701 ) )A701
6X-RAY DIFFRACTION3( CHAIN A AND ( RESID 275:474 OR RESID 702:702 ) )A275 - 474
7X-RAY DIFFRACTION3( CHAIN A AND ( RESID 275:474 OR RESID 702:702 ) )A702
8X-RAY DIFFRACTION4( CHAIN A AND RESID 548:668 )A548 - 668
9X-RAY DIFFRACTION5( CHAIN B AND RESID 2:340 ) OR ( CHAIN G AND RESID 7:64 )B2 - 340
10X-RAY DIFFRACTION5( CHAIN B AND RESID 2:340 ) OR ( CHAIN G AND RESID 7:64 )G7 - 64

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